Disease relevance of nej

• Aberrant histone acetylation, altered transcription, and retinal degeneration in a Drosophila model of polyglutamine disease are rescued by CREB-binding protein [1].
• Sequestration of the transcriptional coactivator CREB-binding protein (CBP), a histone acetyltransferase, has been implicated in the pathogenesis of polyglutamine expansion neurodegenerative disease [1].
• Reductions in CBP activity are the underlying cause of Rubinstein-Taybi syndrome, which is, in part, characterized by several eye defects, including strabismus, cataracts, juvenile glaucoma, and coloboma of the eyelid, iris, and lens [2].
• The CBP tag produced moderate purity protein from E. coli, yeast, and Drosophila extracts, but better purity from HeLa extracts [3].

High impact information on nej

• Recently, we isolated a Drosophila CBP (dCBP) mutant, and found dCBP to be maternally expressed, suggesting that it plays a role in early embryogenesis [4].
• Drosophila CBP represses the transcription factor TCF to antagonize Wingless signalling [5].
• Drosophila CBP is a co-activator of cubitus interruptus in hedgehog signalling [6].
• Trithorax and dCBP acting in a complex to maintain expression of a homeotic gene [7].
• We have purified from Drosophila embryos a trithorax acetylation complex (TAC1) that contains Trx, dCBP, and Sbf1 [7].

Biological context of nej

• We used a yeast genetic screen to identify several ci point mutations that disrupt CI-dCBP interactions [8].
• These mutant proteins are unable to transactivate a reporter gene regulated by ci binding sites and have a lower dCBP-stimulated activity than wild-type CI [8].
• Taken together, our data suggest that dCBP function is necessary for ci-mediated transactivation of wg during Drosophila embryogenesis [8].
• CREB-binding protein (CBP) serves as a transcriptional coactivator in multiple signal transduction pathways [8].
• Thus Trx, dCBP, and Sbf1 are closely linked, physically and functionally, in the maintenance of Hox gene expression [7].

Anatomical context of nej

• Like CBP, TAC1 acetylates core histones in nucleosomes, suggesting that this activity may be important for epigenetic maintenance of gene activity. dCBP and Sbf1 associate with specific sites on salivary gland polytene chromosomes, colocalizing with many Trx binding sites [7].
• In flies, dCBP serves as a coactivator for the transcription factors Cubitus interruptus, Dorsal, and Mad, and as a cosuppressor of Drosophila T cell factor [9].
• We used an uninflated-wing phenotype, caused by the overexpression of dCBP in specific central nervous system cells, to screen for suppressors of dCBP overactivity [10].

Regulatory relationships of nej

• Cubitus interruptus requires Drosophila CREB-binding protein to activate wingless expression in the Drosophila embryo [8].
• In Drosophila S2 cells, the Bcd activity is increased by the co-transfection of plasmids expressing dCBP and reduced by double-stranded RNA-mediated interference against dCBP [11].
• In this report, we provide evidence that dCBP may regulate the formation of chromatin states through interactions with the modulo (mod) gene product, a protein that is thought to be involved in chromatin packaging [9].
• Using immunocolocalization, we showed that the ASH1 protein is specifically expressed in the majority of the dCBP-overexpressing cells, suggesting that these proteins have the potential to interact biochemically [10].
• It appears that a major function of dCBP in the embryo is to regulate upstream components of the Dpp/Screw pathway by Smad-independent mechanisms, as well as acting as a Smad coactivator on downstream target genes [12].

Other interactions of nej

• In this report, we describe experiments to analyze the role of the Drosophila co-activator dCBP in Bcd-mediated activation [11].
• In a two-hybrid screen for proteins that interact with the Drosophila CREB-binding protein (dCBP), a known histone acetyltransferase and transcriptional coactivator, we identified the Drosophila homolog of a yeast chromatin regulator, Sir2 [13].
• The interaction between the coactivator dCBP and Modulo, a chromatin-associated factor, affects segmentation and melanotic tumor formation in Drosophila [9].
• The acetyltransferase activity of CBP is required for wingless activation and H4 acetylation in Drosophila melanogaster [14].
• Smad proteins, the intracellular transducers of the signal, fail to become activated by phosphorylation in dCBP mutants, leading to diminished Dpp/Screw-target gene expression [12].

Analytical, diagnostic and therapeutic context of nej

• Our chromatin immunoprecipitation experiments show that dCBP can increase not only the occupancy of Bcd itself at the enhancers but also the recruitment of general transcription factors to the promoter [11].

References